Vasopressin (antidiuretic hormone, ADH) a nonapeptide hormone and neurotransmitter, is synthesized in the supraoptic nuclei of the hypothalamus of the brain and transported through the supraoptico-hypophyseal tract to the posterior pituitary where it is stored. Upon sensing an increase in plasma osmolality by brain osmoreceptors or a decrease in blood volume or blood pressure (detected by the baroreceptors and volume receptors), vasopressin is released into the blood circulation and activates vasopressin V.sub.1a receptors on blood vessels causing vasoconstriction to raise blood pressure; and vasopressin V.sub.2 receptors of the nephron of the kidney causing reabsorption mainly of water and to a lesser degree electrolytes, to expand the blood volume (Cervoni and Chan, Diuretic Agents, in Kirk-Othmer, Encyclopedia of Chemical Technology, 4th ed., Wiley, Volume 8, 398-432, (1993)). The existence of vasopressin in the pituitary was known as early as 1895 (Oliver and Schaefer, J. Physiol. (London), 18, 277-279, (1895)). The determination of the structure and the total synthesis of vasopressin were accomplished by du Vigneaud and coworkers in 1954 (du Vigneaud, Gish and Katsoyannis, J. Am. Chem. Soc., 76, 4751-4752, (1954)).
The actions of vasopressin V.sub.1a receptors are mediated through the phosphatidylinositol pathway. Activation of vasopressin V.sub.1a receptors causes contraction of the smooth muscle of the blood vessels to raise blood pressure. The actions of the vasopressin V.sub.2 receptors are mediated through activation of the adenylate cyclase system and elevation of intracellular levels of cAMP. The activation of vasopressin V.sub.2 receptors by vasopressin or vasopressin-like (peptidic or non-peptidic) compounds increases water permeability of the collecting ducts of the nephron and permits the reabsorption of a large quantity of free water. The end result is the formation and excretion of a concentrated urine, with a decrease in urine volume and an increase in urinary osmolality.
Vasopressin plays a vital role in the conservation of water by concentrating the urine at the site of the collecting ducts of the kidney. The collecting ducts of the kidney are relatively impermeable to water without the presence of vasopressin at the receptors and therefore, the hypotonic fluid formed after filtering through the glomeruli, passing the proximal convoluted tubule, the loops of Henle, and the distal convoluted tubules, will be excreted as dilute urine. However, during dehydration, volume depletion or blood loss, vasopressin is released from the brain and activates the vasopressin V.sub.2 receptors in the collecting ducts of the kidney rendering the ducts very permeable to water; hence water is reabsorbed and a concentrated urine is excreted. In patients and animals with central or neurogenic diabetes insipidus, the synthesis of vasopressin in the brain is defective and therefore, they produce very little or no vasopressin, but their vasopressin receptors in the kidneys are normal. Because they cannot concentrate the urine, they may produce as much as 10 times the urine volumes of their healthy counterparts and they are very sensitive to the action of vasopressin and vasopressin V.sub.2 agonists. Vasopressin and desmopressin, which is a peptide analog of the natural vasopressin, are being used in patients with central diabetes insipidus. Vasopressin V.sub.2 agonists are also useful for the treatment of nocturnal enuresis, nocturia, urinary incontinence and temporary delay of urination whenever desirable.
Vasopressin, through activation of its V.sub.1a receptors, exerts vasoconstricting effects so as to raise blood pressure. A vasopressin V.sub.1a receptor antagonist will counteract this effect. Vasopressin and vasopressin-like agonists release factor VIII and von Willebrand factor so they are useful for the treatment of bleeding disorders, such as hemophilia. Vasopressin and vasopressin-like agonists also release tissue-type plasminogen activator (t-PA) into the blood circulation so they are useful in dissolving blood clots such as in patients with myocardial infarction and other thromboembolic disorders (Jackson, "Vasopressin and other agents affecting the renal conservation of water", in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 9th ed., Hadman, Limbird, Molinoff, Ruddon and Gilman Eds., McGraw-Hill, New York, pp. 715-731 (1996); Lethagen, Ann. Hematol. 69, 173-180 (1994); Cash et al., Brit. J. Haematol., 27, 363-364 (1974); David, Regulatory Peptides, 45, 311-317 (1993); Burggraaf et al., Cli. Sci., 86, 497-503 (1994)).
The following prior art references describe peptidic vasopressin antagonists: Manning et al., J. Med. Chem., 35, 382 (1992); Manning et al., J. Med. Chem., 35, 3895 (1992); Gavras and Lammek, U.S. Pat. No. 5,070,187 (1991); Manning and Sawyer, U.S. Pat. No. 5,055,448 (1991); Ali, U.S. Pat. No. 4,766,108 (1988); Ruffolo et al., Drug News and Perspectives 4(4), 217 (May 1991); Albright and Chan, Curr. Pharm. Des. 3(6), 615 (1997). Williams et al., have reported on potent hexapeptide oxytocin antagonists [J. Med Chem., 35, 3905 (1992)] which also exhibit weak vasopressin antagonistic activity in binding to V.sub.1 and V.sub.2 receptors. Peptidic vasopressin antagonists suffer from a lack of oral activity and many of these peptides are non-selective antagonists since they also exhibit partial agonist activity.
Non-peptidic vasopressin antagonists have recently been disclosed. Albright et al. describe tricyclic azepines as vasopressin antagonists or vasopressin and oxytocin antagonists in U.S. Pat. No. 5,516,774 (1996), U.S. Pat. No, 5,532,235 (1996), U.S. Pat. No. 5,536,718, U.S. Pat. No. 5,610,156 (1997), U.S. Pat. No. 5,612,334 (1997), U.S. Pat. No. 5,624,923 (1997), U.S. Pat. No. 5,654,297 (1997), U.S. Pat. No. 5,686,445 (1997), U.S. Pat. No. 5,693,635 (1997), U.S. Pat. No. 5,696,112, U.S. Pat. No. 5,700,796 (1997), U.S. Pat. No. 5,719,278 (1998), U.S. Pat. No. 5,733,905 (1998), U.S. Pat. No. 5,736,538 (1998), U.S. Pat. No. 5,736,540 (1998), U.S. Pat. No. 5,739,128 (1998), U.S. Pat. No. 5,747,487 (1998), U.S. Pat. No. 5,753,648 (1998), U.S. Pat. No. 5,760,031 (1998), U.S. Pat. No. 5,780,471 (1998); tetrahydrobenzodiazepine derivatives as vasopressin antagonists are disclosed in J.P. 0801460-A (1996); Ogawa et al., disclose benzoheterocyclic derivatives as vasopressin and oxytocin antagonists, and as vasopressin agonists in WO 9534540-A; and Venkatesan et al., disclose tricyclic benzazepine derivatives as vasopressin and oxytocin antagonists in U.S. Pat. No. 5,521,173 (1996).
As mentioned above, desmopressin (1-desamino-8-D-arginine vasopressin) (Huguenin and Boissonnas, Helv. Chim. Acta, 49, 695 (1966)) is a vasopressin agonist. The compound is a synthetic peptide with variable bioavailability. An intranasal route is poorly tolerated and an oral formulation for nocturnal enuresis requires a 10-20 fold greater dose than the intranasal administration.
Albright et al. disclose (cf. examples 1 and 6), a subset of tricyclic pyrrolo benzodiazepines which are part of the present application, as V.sub.1 and/or V.sub.2 vasopressin receptor antagonists and oxytocin receptor antagonists in U.S. Pat. No. 5,521,173 (1996), inter alia.
Compounds of general structure 7a in Scheme I U.S. Pat. No. 5,521,173 are taught by Albright et al. to possess antagonist activity at V.sub.1 and/or V.sub.2 receptors and exhibit in vivo vasopressin antagonist activity, as well as antagonist activity at oxytocin receptors. ##STR3##
wherein m is 1; Y is a moiety selected from (CH.sub.2).sub.n wherein n is 1; D, E, and F are selected from carbon; A.sup.1 is CH; R.sup.6 is the moiety: ##STR4## PA1 wherein m is 1; Y is a NH or a moiety selected from (CH.sub.2).sub.n wherein n is 1; R.sup.5 and R.sup.7 are selected from hydrogen; X is direct bond; R.sup.10 represents the moiety ##STR7## PA1 Y is a moiety selected independently, from NH or --(CH.sub.2).sub.n -- wherein n is 1; m is aninteger from 1 to 2; PA1 R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are independently, selected from hydrogen, lower alkyl (C.sub.1 -C.sub.6), lower alkoxy (C.sub.1 -C.sub.6), halogen, and CF.sub.3 ; PA1 R.sub.3 and R.sub.4 are independently, selected from the group comprising hydrogen, lower alkyl (C.sub.1 -C.sub.6), halogen, amino, (C.sub.1 -C.sub.6) lower alkoxy, or (C.sub.1 -C.sub.6) lower alkylamino; PA1 and the moiety ##STR10## PA1 represents:
K.sup.1 is CH; X is S; R.sup.5 is hydrogen; R.sup.7 is hydrogen; and the moiety: ##STR5## PA3 represents an optionally substituted phenyl, a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, or a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom.
represents a fused phenyl or optionally substituted phenyl. PA2 p is 0; R.sup.1 and R.sup.2 are selected from hydrogen, (C.sub.1 -C.sub.3) lower alkyl, (C.sub.1 -C.sub.3) lower alkoxy and halogen; and the moiety ##STR8## PA2 (1) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen (wherein A is nitrogen, and B and C are CH); PA2 (2) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen (wherein A is carbon, B is nitrogen, and C is CH--CH); PA2 (3) a 6-membered aromatic (unsaturated) ring (wherein A is carbon, B is CH, and C is --CH--CH--);
Also, Albright et al. broadly disclose a subset of tricyclic pyrrolo and pyrido benzodiazepines, part of the present application, as V.sub.1 and/or V.sub.2 vasopressin receptor antagonists and oxytocin receptor antagonists in WO 96/22282 A1 (1996), inter alia.
Compounds of general structure 61b in Scheme 12 of the above application, are claimed by Albright et al. to possess antagonist activity at V.sub.1 and/or V.sub.2 receptors and exhibit in vivo vasopressin antagonist activity, as well as antagonist activity at oxytocin receptors. ##STR6##
However, certain tricyclic pylrrolo- and pyridobenzodiazepines of general structure 7b and 61b have been found unexpectedly to be vasopressin V.sub.2 receptor agonists in vivo, and thus possess different biological profile and clinical utility from those originally disclosed. Thus, rather than having an aquaretic effect they do unexpectedly cause reabsorption of water, i.e they reduce urine volume and increase urine osmolality.
The compounds of this invention are non-peptidic and have a good oral bioavailability. They are vasopressin V.sub.2 receptor agonists, and as such they promote reabsorption of water. They have no vasopressin V.sub.1a receptor agonist effects so they do not raise blood pressure. In contrast, the prior art compounds are described as vasopressin antagonists at both the V.sub.1a and V.sub.2 receptors.